20 november 2017, holiday inn izdihar ... -...
TRANSCRIPT
GaBI Scientific
Meetings 20 November 2017, Holiday Inn Izdihar Riyadh, Saudi Arabia
First GCC Stakeholder Meeting on Approval Process, Interchangeability/Substitution and Safety of Biosimilars
Assistant Professor Gianluca Trifirò MD, PhD, Italy
• Clinical Pharmacologist and Assistant Professor of Pharmacology, Department of Clinical and Experimental Medicine, University of Messina, Italy
• Honorary Assistant Professor of Pharmacoepidemiology, Department of Medical Informatics, Erasmus University Medical Center Rotterdam, The Netherlands
• External Consultant of the Scientific Secretariat, Pharamcovigilance Office, Italian Medicines Agency (AgenziaItaliana del Farmaco, AIFA)
GaBI Scientific
Meetings 20 November 2017, Holiday Inn Izdihar Riyadh, Saudi Arabia
First GCC Stakeholder Meeting on Approval Process, Interchangeability/Substitution and Safety of Biosimilars
The false myths of biosimilars
Assistant Professor Gianluca Trifirò, MD, PhD
20 November 2017
Prof. Gianluca Trifirò
Dpt. Scienze Biomediche, Odontoiatriche e Immagini Morfologiche e Funzionali, Università di Messina (Italy)
Dpt. Medical Informatics, Erasmus Medical Center, Rotterdam (Netherlands)
The false myths about biosimilars
First GCC Stakeholder Meeting on Approval Process, Interchangeability/Substitution and Safety of Biosimilars
20 November 2017, Riyadh, Saudi Arabia
Disclaimer
• I have been part of advisory boards on biosmilars organized by Sandoz and Hospira
• As scientific coordiniator of an academic pharmacoepi team I have been coordinating observational studies on biological drugs which have been funded by several pharmaceutical companies, e.g. Amgen, Novartis, Daiichi Sankyo
Myths
Bio-identicality versus similarity
Pre-marketing evidence on benefit-risk profile of biosimilars
Post-marketing safety of biosimilars
Interchangeability of biosimilar and reference product
Biologic drugs Biologic drug: substance made from living organism or its products, e.g. vaccines, blood components, gene therapies, antibodies, interleukins, and living cells used in cell therapy
Biotechnology: use of living systems and organisms to develop therapeutic proteins
EMA definition of biosimilars
“A biosimilar is a biological medicinal product that contains a version of the active substance of an already authorised original biological medicinal product (reference medicinal product) in the EEA. Similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise needs to be established”
1. EMA. http://www.ema.europa.eu/../WC500176768.pdf [Accessed May 2015].
Abbreviation: EEA: European economic area
FDA: follow-on biologics
65 MAAs submitted to EMA
12 MAAs under review - Adalimumab (2) - Bevacizumab (2) - Infliximab (1) - Insulin glargine (1) - Pegfilgrastim (3) - Trastuzumab (3)
53 MAAs reviewed
41 authorized
3 withdrawn post-approval
- Filgrastim (2) - Somatropin
38 valid MA’s - Adalimumab (4) - Enoxaparin (2) - Epoetin (5) - Etanercept (2) - Filgrastim (7) - Follitropin (2) - Infliximab (3) - Insulin glargine (2) - Insulin lispro (1) - Rituximab (6) - Somatropin (1) - Teriparatide (2) - Trastuzumab (1)
10 withdrawn - Epoetin (1) - Insulin (6) - Pegfilgrastim (3)
www.ema.europa.eu 21/10/2017
2 refuted - Interferon alfa-2a - Human insulin
The false myths about biosimilars – 1 Bio-identicality vs. similarity
«Biosimilars are not identifical but only similar to reference product, thus they are
to be considered as different drugs»
Biologicals are similar but not identical
Disclaimer: Hypothetic mAb production
Bio
logi
cal a
ctiv
ity
(ug
/ml)
1500
1000
500
Acceptable
Variation
for the
company,
for EMA,
for FDA
Year 1 Year 2 Year 3 Year 4 ………..
The false myths about biosimilars – 2 Pre-marketing evidence on benefit-risk profile of biosimilars
«The pre-marketing evidence on biosimilars are much more limited than what is
available for reference product at the time the drug is marketed»
The false myths about biosimilars – 3 Postmarketing safety of biosimilars
«As a result of the limited pre-marketing evidence, biosimilars are less safe than
reference product in routine care»
“Tungsten-mediated unfolding and aggregation of epoetin alfa in pre-filled syringes as a potential root cause for increased immunogenicity” Pharm Res 2012 Jun; 29(6): 1454–1467.
ASL Caserta (N= 1,059,831)
Regione Toscana (N= 4,127,900)
ULSS 9 Treviso (N= 462,642)
ASP Palermo (N= 1,340,746)
Regione Umbria (N = 948,755)
Regione Lazio (N = 5,882,000)
Overall population in the years 2009-2014:
13,293,874 (25% Italian popuation)
N. users of epoetins in the years 2009-2014:
N= 76,654 Lazio: N=21,955
Caserta: N= 7,170 Toscana: N= 34,668 Treviso: N= 1,581
Palermo: N= 6,072 Umbria: 5,208
N. users of G-CSFs in the years 2009-2014:
N= 47,317 Lazio: N=18,234
Caserta: N= 4,369
Palermo: N= 4,841
Toscana: N= 16,109
Treviso: N= 1,619
Umbria: N= 2,145
N. users of somatotropin in the years 2009-2014:
N= 6,785 Lazio: N=2,682
Caserta: N= 282 Toscana: N= 2,046
Treviso: N= 130 Palermo: N= 695 Umbria: N= 242
Assessment of short and long term risk-benefit profile of biologics/biosimilars through healthcare database network in Italy
Italian society of pharmacology position paper
All published studies so far on most of the indications of use of biosimilars did not suggest any difference of biosimilars vs. reference product with respect to safety;
Biosimilars have been increasingly prescribed in Europe since more than 10 years and no major safety issues have been encountered so far;
Several mandatory Post Authorization Safety Studies (PASS) have been carried out and occasionally published which did not lead tto changes in the marketing authorization of biosimilars;
EMA examined a large number of Periodic Safety Update Reports and did not identify any critical issue regarding similarity of benefict-risk profile of biosimilars and reference products.
Società Italiana di Farmacologia. Revisione della posizione sui farmaci biosimilari da parte della Società Italiana di Farmacologia: Working Paper 2014. 2014. Availableonline: http://www.sifweb.org/docs/sif_position_paper_revisione_biosimilari_lug14.pdf.
The false myths about biosimilars – 4 Interchangeability of biosimilar and reference product
«Interchangeability of biosimilars and reference product is an issue to be never considered due to
serious immunogenicity risks potentially associated with switching of therapeutic proteins»
Definitions
Interchangeability: possibility of exchanging one medicine for another medicine that is expected to have the same clinical effect. This could mean replacing a reference product with a biosimilar (or vice versa) or replacing one biosimilar with another;
Switching: it is when the prescriber decides to exchange one medicine for another medicine with the same therapeutic intent;
Substitution (automatic): the practice of dispensing one medicine instead of another equivalent and interchangeable medicine at pharmacy level without consulting the prescriber.
Adapted by presentation from S. Madsen (Norway Drug Agency) – 15th Medicines for Europe conference on Biosimilars - London 23-24/3/2017
Switching will be an increasingly complex issue
Switch between various ESAs during first year of therapy in 5 Italian Regions, years 2009-2014
20% incident ESA users switched to other ESAs during first year therapy
Ingrasciotta Y et al. How Much Are Biosimilars Used in Clinical Practice? A Retrospective Italian Population-Based Study of Erythropoiesis-Stimulating Agents in the Years 2009-2013. BioDrugs. 2015;29(4):275-84.
In addition to the studies demonstrating biosimilarity, it is requested to conduct pre-marketing studies on multiple and reverse switching of biosimilar and reference products to grant the biosimilar with interchangeable status;
FDA draft guidance for industries contains detailed requests for the demonstration of interchangeability between biosimilars and reference products. This draft requires the evaluation of at least three switches between reference product and biosimilar (back and forward).
FDA. Considerations in Demonstrating Interchangeability With Reference Product Guidance for Industry. 2017
“Our conclusion is that a state-of-the-art demonstration of biosimilarity, together with intensified post-marketing
surveillance, is a sufficient and realistic way of ensuring interchangeability of EU-approved biosimilars under
supervision of the prescriber.”
Kurki et al. 2017. BioDrugs 2017. ePub
ECCO Position Statement on the Use of Biosimilars for IBD Switching from the originator to a biosimilar in patients with IBD is
acceptable. Studies of switching can provide valuable evidence for safety and efficacy. Scientific and clinical evidence is lacking regarding reverse switching,
multiple switching, and cross-switching among biosimilars in IBD patients. Danese S et al. ECCO Position Statement on Use of Biosimilars for Inflammatory Bowel Disease-An Update. J Crohns Colitis 2017:26-34.
Future challenges
Growing number of II generation biosimilars will be shortly marketed, which requires post-marketing short- and long-term monitoring;
To evaluate benefit and risks of switching between originators and biosimilars (and viceversa) in post-marketing setting to integrate pre-marketing evidence on interchangeability;
To consider secondary use of healthcare databases for rapid and cost-saving surveillance of biosimilars in routine care;
Payers, healthcare professionals and patients have to be all involved in the RWE generation about biologics and biosimilars to be integrated with premarketing RCT evidence.
Thanks for the attention
Gianluca Trifirò
[email protected] [email protected]
“The human mind is like a parachute. It works better when it is open”. Paul Jansen